Method for producing solifenacin or salts thereof

ABSTRACT

There is provided a novel method for producing solifenacin or a salt thereof which is useful as a medicine, particularly a therapeutic agent and/or a preventive agent for a urinary organ system disease such as pollakiuria or urinary incontinence. Illustratively, there are provided (1) a method for producing solifenacin in which 2-(1H-Imidazolylcarbony1)-1-phenyltetrahydroisoquinoline is used as the starting material, (2) a method for producing solifenacin succinate in which (1RS)-phenyltetrahydroisoquinoline-carboxylic acid quinuclidinyl ester is used as the starting material, (3) a method for producing solifenacin in which a lower alkyl quinuclidinyl carbonate is used as the starting material and (4) a method for producing solifenacin in which phenyltetrahydroisoquinoline-carboxylic acid secondary lower alkyl or tertiary lower alkyl ester is used as the starting material and allowed to react with an alkali metal lower alkoxide.

This application is a 371 of PCT/JP05/07771 filed Apr. 25, 2005.

TECHNICAL FIELD

This invention relates to a novel method for producing solifenacin or asalt thereof which is useful as a medicine, particularly a muscarine M₃receptor antagonist, more illustratively a therapeutic agent and/or apreventive agent, for example, a therapeutic agent or the like for aurinary organ disease such as pollakiuria, urinary incontinence or thelike accompanied by overactive bladder.

TECHNICAL BACKGROUND

Chemical name of solifenacin is(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester, and it has the following chemicalstructure.

Solifenacin or a salt thereof is a compound known as a muscarine M₃receptor antagonist (Patent Reference 1, Non-patent Reference 1,Non-patent Reference 2, Non-patent Reference 3) and is on the market asa therapeutic agent for pollakiuria and urinary incontinence accompaniedby overactive bladder. In addition, its usefulness for interstitialcystitis (Patent Reference 2), tension alleviation of ciliary muscle(Patent Reference 3), irritable bowel syndrome (Non-patent Reference 4)and the like has also been reported.

Regarding solifenacin or a salt thereof, the following production methodX and production method Y are specifically known (Patent Reference 1).

(a) Production Method X

(b) Production Method Y

In addition, the following production method is known as a method forproducing compounds having similar structures, but there is no case inwhich this production method was applied to the production ofsolifenacin (Patent Reference 4).

(c) Production Method Z

[In the formulae, Alk represents methyl or ethyl.]

-   Patent Reference 1: International Publication WO 96/20194-   Patent Reference 2: International Publication WO 2003/6019-   Patent Reference 3: JP-A-2002-104968-   Patent Reference 4: JP-A-2003-267977-   Non-patent Reference 1: Current Opinion in Central & Peripheral    Nervous System Investigational Drugs, 2000, vol. 2, no. 3, pp.    321-325-   Non-patent Reference 2: Drugs of the Future, 1999, vol. 24, no. 8,    pp. 871-874-   Non-patent Reference 3: Naunyn-Schmiedeberg's Archives of    Pharmacology, 2002, vol. 366, no. 2, pp. 97-103-   Non-patent Reference 4: Japanese Journal of Pharmacology, 2001, vol.    86, no. 3, pp. 281-288

DISCLOSURE OF THE INVENTION

Problems that the Invention is to Solve

However, as is described later, there were various problems regardingthe production method X and production method Y of solifenacin or a saltthereof, so that concern has been directed toward the development of amethod for producing solifenacin or a salt thereof, which is moreefficient from the viewpoint of industrial production.

Means for Solving the Problems

The present inventors have conducted intensive studies on a new methodfor producing solifenacin or a salt thereof and found as a result thatsolifenacin or a salt thereof can be produced efficiently by theproduction method shown in the following, thereby resulting in theaccomplishment of the invention.

That is, according to the invention, novel methods for producingsolifenacin or a salt thereof shown in the following are provided.

1. A method for producing solifenacin or a salt thereof, which comprisesallowing a compound represented by a formula (I)

[in the formula, Lv represents 1H-imidazol-1-yl,2,5-dioxopyrrolidin-1-yloxy, 3-methyl-1H-imidazol-3-ium-1-yl or chloro]and (R)-quinuclidin-3-ol to undergo condensation.

As the Lv, 1H-imidazol-1-yl is desirable.

2. A method for producing solifenacin succinate, which comprisesallowing succinic acid to react with a compound represented by a formula(II)

[in the formula, stereochemistry of the 1-position of phenyl-substitutedtetrahydroisoquinoline is a mixture of (R)-form and (S)-form].

3. A method for producing solifenacin or a salt thereof, which comprisesallowing a compound represented by a formula (III)

[in the formula, R¹ represents a lower alkyl which may be substituted]and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof toundergo condensation.

As R², ethyl is preferable.

4. A method for producing solifenacin or a salt thereof, which comprisesallowing a compound represented by a formula (IV)

[in the formula, R² represents a secondary lower alkyl or a tertiarylower alkyl, which may be respectively substituted] and(R)-quinuclidin-3-ol to undergo reaction in the presence of an alkalimetal lower alkoxide.

As the R², isopropyl or tert-butyl is desirable.

In addition, as the lower alkoxide of the alkali metal lower alkoxide, asecondary lower alkoxide or a tertiary lower alkoxide is desirable, anda secondary lower alkoxide or tertiary lower alkoxide which correspondsto R² is particularly desirable.

EFFECT OF THE INVENTION

(1) Production Method 1

[In the formula, Lv represents 1H-imidazol-1-yl,2,5-dioxopyrrolidin-1-yloxy, 3-methyl-1H-imidazol-3-ium-1-yl or chloro.]

This production method is a method for producing solifenacin, which uses(S)-2-(1H-imidazol-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline,1-({[(S)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl]carbonyl}oxy)pyrrolidine-2,5-dione,(S)-2-(3-methyl-1H-imidazol-3-ium-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline,or (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl chloride,instead of the (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylicacid ethyl ester used in the aforementioned production method Y as thestarting material.

Since ethyl carboxylate is used as the starting material in theproduction method Y, ethanol (EtOH) is by-produced, and the by-producedEtOH launches a nucleophilic attack against the intended substancesolifenacin in the presence of a base. Thus, it is necessary to carryout the reaction while removing EtOH from the reaction system, forexample by the toluene azeotrope or the like, so that control of thereaction, particularly control of the evaporated amount of the solventby distillation is essential, but such a control is very difficult toeffect. However, According to this production method, imidazole,1-hydroxypyrrolidine-2,5-dione, 3-methyl-1H-imidazol-3-ium orhydrochloric acid is by-produced, but these by-produced compounds do notlaunch a nucleophilic attack against the intended substance solifenacinin the presence of a base, and control of the reaction is not necessary.

In addition, when the production method Y was compared at a certainsimilar degree of scale with a method which uses(S)-2-(1H-imidazol-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline,it was found that the production method Y requires approximately 8 hoursof reaction time, and what is more, approximately from 5 to 15% of thestarting material(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethylester remains, while the reaction time of this production method can beshortened by a factor of about 3 hours, and what is more, the startingmaterial(S)-2-(1H-imidazol-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinolineremains only about 0.3%. in addition, while solifenacin exists in fouroptical isomer forms due to the presence of 2 asymmetric centers,production of undesired optical isomers was about 7% by the productionmethod Y, but production of undesired optical isomers was about 1% orless by the present production method.

Accordingly, this production method is a superior production method incomparison with the production method Y from the viewpoints that (i)control of the reaction is easy because it is not necessary to removereaction byproducts from the reaction system, that (ii) the reactiontime can be sharply shortened, that (iii) remaining of the startingmaterial after completion of the reaction can be sharply reduced, andthat (iv) formation of undesired optical isomers by the side reactioncan be sharply reduced.

(2) Production Method (2)

This method is a method for producing optically active solifenacinsuccinate by using a diastereomer mixture(1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester as the material and carrying out opticalresolution accompanied by the salt formation with succinic acid.

Conventionally, in carrying out production of solifenacin or a saltthereof, optically active solifenacin or a salt thereof was produced byproducing solifenacin through the bonding of an optically active1-phenyl-1,2,3,4-tetrahydroisoquinoline unit with a quinuclidin-3-olunit, and applying a salt formation reaction to the optically activesolifenacin as occasion demands.

However, in order to produce the optically active1-phenyl-1,2,3,4-tetrahydroisoquinoline unit to be used as a startingmaterial, it was essential to employ an operation such as opticalresolution using tartaric acid, a reaction using an asymmetric catalyst,a resolution using chiral column or the like. In addition, such anoperation which becomes necessary when produced as an optically activesubstance increases the number of steps in the industrial productionprocess and also becomes a cause of making the operation more complex.

On the other hand, according to this production method, atetrahydroquinoline 1-position diastereomer mixture can be used as the1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acidquinuclidin-3-yl ester before carrying out a salt formation reaction, sothat it is able to omit steps which are necessary in producing theoptically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline unit, such assalt formation using an acid having asymmetric center, opticalresolution and subsequent desalting; asymmetric synthesis using anexpensive asymmetric catalyst; and/or separation by a chiral column; andthe like. That is, according to the invention, the number of steps canbe shortened in the industrial production process so that solifenacinsuccinate can be produced more efficiently.

In addition, it is very surprising that a desired optical isomer alonecan be separated merely by an operation to make a salt of a diastereomermixture using succinic acid or the like acid or base having noasymmetric center.

Thus, this production method is (i) an efficient and excellentproduction method from the viewpoint that the operations generallynecessary in producing the solifenacin starting material,1-phenyl-1,2,3,4-tetrahydroisoquinoline unit, as an optically activesubstance are not required because it is not necessary to produce it asan optically active substance, and is (ii) a quite surprising productionmethod from the viewpoint that solifenacin succinate as a desiredoptical isomer can be separated by making a diastereomer mixture,(1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester, into a salt using succinic acid which doesnot have asymmetric center.

(3) Production Method 3

[In the formula, R¹ represents a lower alkyl which maybe substituted.]

This production method is a method for producing solifenacin, which usesan lower alkyl (R)-quinuclidin-3-yl carbonate instead of the(R)-quinuclidin-3-yl chloroformate used in the aforementioned productionmethod X as the starting material.

In the production method X, chloroformate is used as the startingmaterial, and this chloroformate is produced from (R)-quinuclidin-3-oland phosgene or a phosgene derivative. As the phosgene derivative,diphosgene and triphosgene can be exemplified. However, since it isknown that phosgene causes a respiratory organ disorder when inhaled, itis difficult to use it in the industrial production. Even whendiphosgene, triphosgene or the like phosgene derivative is used, iteasily forms phosgene when decomposed, so that it cannot be said thatthis is suited for the industrial production. Also, this type ofreaction requires control of the reaction in an atmosphere of argon,nitrogen or the like inert gas under a non-aqueous condition, so thatthe operation becomes complex. In addition, since quinuclidinylchloroformate is apt to be decomposed, it becomes necessary to prepareit when used.

On the other hand, according to the present production method, a loweralkyl quinuclidinyl carbonate is used as the active species, which canbe produced from quinuclidinol and a lower alkyl chlorocarbonate safelyin view of industrial production and also easily with high yield, and itis not necessary to prepare the lower alkyl quinuclidinyl carbonate atthe time of its use, because the compound is stable at from lowtemperature to ordinary temperature.

Accordingly, this production method is a superior production method incomparison with the production method X from the viewpoints that (i)since phosgene or a phosgene derivative having extremely high toxicityis not used, this is excellent in safety in view of industrialproduction, that (ii) since a inert gas atmosphere and a non-aqueouscondition are not required for the production of a lower alkyl carbonatequinuclidine ester as the active species, the production steps do notbecome complex, and that (iii) since the lower alkyl quinuclidinylcarbonate as the active species is stable at from low temperature toordinary temperature, its storage is possible and its preparation whenused is not necessary.

(4) Production Method 4

[In the formula, R² represents a secondary lower alkyl or a tertiarylower alkyl, which may be respectively substituted.]

This production method is a method for producing solifenacin, which usesan alkali metal lower alkoxide instead of the sodium hydride used as abase in the aforementioned production method Y, and also uses an(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid secondarylower alkyl or tertiary lower alkyl ester, wherein said alkyl may berespectively substituted, instead of the(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethylester used as the starting material in the aforementioned productionmethod Y.

Sodium hydride is used in the production method Y, which has a danger ofcausing firing and a problem of causing contamination with thecontaining mineral oil. However, this production method is characterizedby the use of an alkali metal lower alkoxide which does not have suchproblems.

In addition, as shown in the following Reference Example 2, ReferenceExample 3 and Reference Example 4, it was confirmed that whensolifenacin is produced using ethyl ester, methyl ester, benzyl ester orthe like substitutable primary lower alkyl ester of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid as thestarting material, a compound in which a primary lower alkyl which maybe substituted is added to the solifenacin 2′-position, namely thequinuclidine 2-position, is by-produced as an impurity. On the otherhand, by-production of a compound in which a primary lower alkyl whichmay be substituted is added to the solifenacin 2′-position, namely thequinuclidine 2-position, found in Reference Example 2, Reference Example3 and Reference Example 4, was not found by this production method, dueto the use of a respectively substitutable secondary lower alkyl ortertiary lower alkyl, namely R², ester of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid as thestarting material. Especially, when a secondary lower alkoxide, atertiary lower alkoxide or a lower alkoxide which corresponds to R² wasused as the lower alkoxide of the alkali metal lower alkoxide,by-production of the compound in which a lower alkyl was added to theaforementioned quinuclidine 2-position was not found.

Accordingly, this production method is (i) a superior method incomparison with the production method Y from the viewpoint that analkali metal lower alkoxide having reduced danger in the industrialproduction can be used, and is (ii) a quite surprising production methodfrom the viewpoint that, in comparison with the production method inwhich ethyl ester, methyl ester, benzyl ester or the like substitutableprimary lower alkyl ester of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid is used asthe starting material, a compound in which a lower alkyl is added to thequinuclidine 2-position is not by-produced in the solifenacin-containingcomposition produced by this production method which uses a respectivelysubstitutable secondary lower alkyl or tertiary lower alkyl ester of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid as thestarting material.

BRIEF DESCRIPTION OF THE INVENTION

FIG. 1 is a chart in which the composition concerning compound A,compound B and compound C of the solifenacin obtained in ReferenceExample 1 was measured by HPLC. The peak of about 33.3 minutes inretention time shows solifenacin, and the peaks of about 15.6 minutes,about 19.8 minutes and about 16.9 minutes in retention time respectivelyshow the compound A, compound B and compound C.

FIG. 2 is a chart in which the composition concerning compound A,compound B and compound C of the solifenacin-containing EtOAc solutionobtained in Reference Example 2 was measured by HPLC. The peak of about32.5 minutes in retention time shows solifenacin, and the peaks of about17.9 minutes, about 21.5 minutes and about 19.1 minutes in retentiontime respectively show the compound A, compound B and compound C.

FIG. 3 is a chart in which the composition concerning compound A,compound B and compound C of the solifenacin before salt formation withsuccinic acid, obtained in Example 1A, was measured by HPLC. The peak ofabout 32.4 minutes in retention time shows solifenacin, and the peaks ofabout 17.4 minutes and about 21.0 minutes in retention time respectivelyshow the compound A and compound B.

FIG. 4 is a chart in which the composition concerning compound A andcompound B of the solifenacin succinate obtained in Example 2 wasmeasured by HPLC. The peak of about 32.0 minutes in retention time showssolifenacin, and the peaks of about 17.5 minutes and about 21.1 minutesin retention time respectively show the compound A and compound B.

BEST MODE FOR CARRYING OUT THE INVENTION

The following further describes the invention.

The term “lower alkyl” as used herein means a straight chain or branchedchain C₁₋₆ alkyl, and its illustrative examples include methyl, ethyl,propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl and the like.

Accordingly, methyl, ethyl, n-propyl, n-butyl, 2-methylpropan-1-yl andthe like can be cited as illustrative examples of the “primary loweralkyl”, and isopropyl, butan-2-yl, pentan-3-yl, tert-butyl,2-methylbutan-2-yl, 3-methylpentan-3-yl and the like can be cited asillustrative examples of the “secondary lower alkyl or tertiary loweralkyl”.

In addition, the “lower alkoxide” is an —O-lower alkyl which correspondsto the aforementioned lower alkyl. Accordingly, methoxy, ethoxy,n-propoxy, n-butoxy, 2-methylpropan-1-yloxy and the like can be cited asillustrative examples of the “primary lower alkoxide,” and 2-propoxy,butan-2-yloxy, pentan-3-yloxy, tert-butoxy, 2-methylbutan-2-yloxy,3-methylpentan-3-yloxy and the like can be cited as illustrativeexamples of the “secondary lower alkoxide or tertiary lower alkoxide”.

The acceptable substituent group of R¹ and R² may be any group which isgenerally acceptable to be substituted to lower alkyl, and phenyl andthe like can be illustratively cited. In this connection, in the“primary lower alkyl”, its carbon atom having linking arm is substitutedby at least 2 hydrogen atoms.

The “alkali metal lower alkoxide” is a salt of an alcohol whichcorresponds to the aforementioned lower alkyl with an alkali metal, andlithium, sodium, potassium and the like can be exemplified as the alkalimetal, of which sodium or potassium is preferred. As the “alkali metallower alkoxide”, sodium methoxide, sodium ethoxide, sodium propoxide,sodium isopropoxide, sodium butoxide, sodium tert-butoxide, sodiumbenzyloxide, potassium methoxide, potassium ethoxide, potassiumtert-butoxide and the like can be illustratively exemplified. In thisconnection, regarding the alkali metal lower alkoxide to be used in theproduction, it is desirable to use an alkali metal lower alkoxide whichcorresponds to the —O-lower alkyl group existing in the molecule of thestarting material.

The “base” may be any base which is sufficient enough for the hydroxylgroup of quinuclidinol or the amino group of tetrahydroisoquinolin tocarry out nucleophilic attack, and its illustrative examples include analkali metal lower alkoxide; sodium hydroxide, potassium hydroxide orthe like hydroxide; sodium hydride, potassium hydride, lithium hydrideor the like hydride; triethylamine, diisopropylethylamine or the liketertiary amine; lithium diisopropylamide, potassiumhexamethyldisilazide, sodium hexamethyldisilazide, butyl lithium or thelike alkali metal reagent; or the like, and the production can also becarried out by adding 4-(N,N-dimethylamino)pyridine or the likecatalyst.

The “salt thereof” of the “solifenacin or a salt thereof” may be anysalt of solifenacin with a pharmacologically acceptable acid, andillustratively, an acid addition salt with hydrochloric acid, sulfuricacid or the like inorganic salt; or with succinic acid, acetic acid,oxalic acid, malonic acid or the like organic acid; can be exemplified.Preferred as the “solifenacin or a salt thereof” is solifenacin orsolifenacin succinate.

Also, the term percentage content as used herein represents the ratio ofarea of each substance measured by an HPLC analysis when solifenacin ora salt thereof is defined as 100%, and is a percentage content measuredby the HPLC analysis under the conditions shown in Examples which aredescribed later or under conditions proportional thereto. In thisconnection, each of the substances is detected as a basic substanceresulting from the removal of the addition salt.

In addition, the invention also includes a production method and acomposition, which uses a compound, so-called labeled compound, in whichthe atoms that constitute solifenacin, a starting material thereofand/or the solifenacin derivative represented by the aforementioned (I)are partially or entirely replaced by a radioisotope.

The production method 1 is a method for producing solifenacin, in which(S)-2-(1H-imidazol-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline,1-({[(S)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl]carbonyl}oxy)pyrrolidine-2,5-dione,(S)-2-(3-methyl-1H-imidazol-3-ium-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinolineor (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl chloride isallowed to react with (R)-quinuclidin-3-ol in the presence of a base.

The reaction can be carried out in a reaction inert solvent, such asbenzene, toluene, xylene, mesitylene and the like aromatic hydrocarbons;diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and the like ethers; dichloromethane,1,2-dichloroethane, chloroform and the like halogenated hydrocarbons;N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone,dimethyl sulfoxide and the like aprotic polar solvents; and the like ora mixture thereof, using equimolar of said starting materials or one ofthem in an excess amount, and at from cooling to room temperature, fromroom temperature to heating or from heating to under reflux, and it isdesirable to carry it out from under heating to under reflux. The basecan be used in an equivalent to excess amount, and it is desirable tocarry out the reaction using a hydride, preferably sodium hydride.

In this connection, the Lv in the aforementioned formula, whichrepresents 1H-imidazol-1-yl, 2,5-dioxopyrrolidin-1-yloxy,3-methyl-1H-imidazol-3-ium-1-yl or chloro, is preferably1H-imidazol-1-yl, 2,5-dioxopyrrolidin-1-yloxy or3-methyl-1H-imidazol-3-ium-1-yl, most preferably 1H-imidazol-1-yl.

In addition,(S)-2-(1H-imidazol-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline,1-({[(S)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl]carbonyl}oxy)pyrrolidine-2,5-dione,(S)-2-(3-methyl-1H-imidazol-3-ium-1-ylcarbonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinolineor (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl chloride canbe produced by carrying out condensation of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline with1,1′-carbonyldiimidazole, N,N′-disuccinimidyl carbonate, phosgene or aphosgene derivative or with 1-methylimidazole, phosgene or a phosgenederivative in accordance with a usual method.

The production method 2 is a method for producing solifenacin succinatein which succinic acid is allowed to react with(1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester.

The solvent to be used in the reaction may be any solvent which isgenerally used in a reaction in which a basic substance such assolifenacin is converted into its acid addition salt, and an organicsolvent, water or a mixture thereof can be exemplified. Moreillustrative examples include methanol, EtOH, 1-propanol, 2-propanol,1-butanol, 2-butanol, tert-butanol and the like alcohols; ethyl acetate(EtOAc), n-propyl acetate, n-butyl acetate, methyl propionate, ethylpropionate and the like esters; ethers; acetone, methyl ethyl ketone andthe like ketones; aprotic polar solvents; acetonitrile; halogenatedhydrocarbons; aromatic hydrocarbons; hexane, heptane and the likesaturated hydrocarbons; water and the like, or a mixed solvent ofoptional species of solvents selected from them. Preferred are mixedsolvents of alcohols and esters, and particularly preferred among themis a mixed solvent of EtOH and EtOAc.

Succinic acid can be used in an equivalent amount of an excess amount.In addition, succinic acid can also be dissolved by adding it and thenheating it when dissolved. Solifenacin succinate as the desired one ofthe stereoisomers can be obtained when the thus obtained solution iscooled, and the resulting precipitate is collected by filtration in theusual way, washed using an appropriate solvent and then dried. In thiscase, though it depends on the scale of the process, it is desirablethat the cooling rate is not rapid.

Also, regarding the solvent to be used in the washing, any solvent whichhas small solubility for solifenacin succinate can be used, andpreferred are ethers, esters and alcohols or a mixed solvent of two ormore solvents selected from the group consisting of these solvents. Thedrying can be carried out by heating, under a reduced pressure or byheating under a reduced pressure.

In addition, the(1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester can be produced, for example, by employingthe method described in the Patent Reference 1, and the followingproduction methods can be exemplified illustratively.

By one of them, the racemic compound (I) can be produced by allowing the(R)-quinuclidin-3-yl chloroformate represented by C or a salt thereof,which is derived by 1 step from commercially available(R)-quinuclidin-3-ol, to react with the racemic tetrahydroisoquinolinrepresented by A or a salt thereof in the presence of a base or in abasic solvent. Illustratively, the method described in Example 7 of theaforementioned Patent Reference 1 can for example by employed.

As another embodiment, the production method by step 2-1 and step 2-2can be cited. The racemic compound (I) can be produced by allowingcommercially available (R)-quinuclidin-3-ol to react, in the presence ofa base or in a basic solvent, with a carbamate represented by B which isobtained by allowing ethyl chloroformate represented by D to react withthe racemic tetrahydroisoquinolin represented by A or a salt thereof inthe presence of a base or in a basic solvent. Illustratively, the methodof Reference Example 1 or Example 8 of the aforementioned PatentReference 1 can for example be employed.

In addition, (1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylicacid (3R)-quinuclidin-3-yl ester can also be produced by employing thesolifenacin production method 1, production method 3 or productionmethod 4 of the invention.

The production method 3 is a method for producing solifenacin in which(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline is allowed to react with anlower alkyl (R)-quinuclidin-3-yl carbonate.

The reaction can be carried out in a reaction inert solvent, such as ofaromatic hydrocarbons; ethers; halogenated hydrocarbons; aprotic polarsolvents; and the like, or a mixture thereof, using said startingmaterials at equimolar level or one of them in an excess amount,preferably equimolar level. In addition, the reaction can be carried outat a temperature of from cooling to room temperature, from roomtemperature to heating, or from heating to under reflux, and it isdesirable to carry out the reaction under reflux while evaporating thesolvent. The base can be used in an amount of from a catalyticallyeffective amount to an excess amount, preferably from 0.1 to 2.0equivalents, more preferably from 0.1 to 1.0 equivalent, furtherpreferably from 0.2 to 0.6 equivalent. It is desirable to carry out thereaction using an alkali metal lower alkoxide, preferably an alkalimetal lower alkoxide which corresponds to R¹.

The production method 4 is a method for producing solifenacin in which(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid secondarylower alkyl or tertiary lower alkyl ester is allowed to react with(R)-quinuclidin-3-ol in the presence of an alkali metal lower alkoxide.

The reaction can be carried out in a reaction inert solvent, such as ofaromatic hydrocarbons; ethers; halogenated hydrocarbons; aprotic polarsolvents; and the like, or a mixture thereof, using said startingmaterials at equimolar level or one of them in an excess amount, at atemperature of from cooling to room temperature, from room temperatureto heating, or from heating to under reflux, and it is desirable tocarry out the reaction under reflux while evaporating the solvent. Thealkali metal lower alkoxide can be used in an amount of from acatalytically effective amount to an excess amount, but it is desirableto use preferably from 0.1 to 1.2 equivalents, more preferably from 0.15to 0.4 equivalent, of an alkali metal lower alkoxide, and it isdesirable to carry out the reaction using an alkali metal lower alkoxidewhich corresponds to R².

EXAMPLES

The following illustratively describes the invention based on Examples,but the invention is not restricted by these Examples.

Reference Example 1

A mixture of 8 liters of water and 3.17 kg of potassium carbonate wasadded to a mixture of 4.00 kg of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 40 liters of toluene,and 2.49 kg of ethyl chloroformate was added dropwise thereto andstirred for 2 hours. A 20 liter portion of water was added to thisreaction solution, the water layer was separated, and the organic layerwas washed with 20 liters of water. After evaporation of the solventunder a reduced pressure, 43.7 liters of toluene and 4.9 liters of DMFwere added thereto, and 2.64 kg of (R)-quinuclidin-3-ol and 0.188 kg ofsodium hydride were added thereto at room temperature and heated for 8hours while evaporating the solvent. A 49 liter portion of toluene and25 liters of water were added to this reaction mixture which wassubsequently cooled to room temperature, and then the water layer wasseparated and the organic layer was washed with 25 liters of water. Thisorganic layer was then extracted with 49 liters of 4% hydrochloric acid,the thus obtained water layer was mixed with 5.8 kg of potassiumcarbonate and extracted with EtOAc, and the organic layer wasconcentrated under a reduced pressure to obtain 5.32 kg of(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester (to be referred to as “solifenacin”hereinafter).

The optical isomer content of the solifenacin obtained in ReferenceExample 1 is shown in Table 1 as the percentage content when solifenacinis defined as 100%. Also, measured data of the determination of thecomposition concerning compound A, compound B and compound C as opticalisomers of the solifenacin obtained in Reference Example 1 is shown inFIG. 1.

In this connection, the compound A, compound B and compound C have thefollowing structures.

In this connection, determination of the compound A, compound B andcompound C was carried out by the following method.

A 0.25 g portion of the obtained composition was dissolved in a mixedliquid of hexane/2-propanol (1:1), and the total volume was adjusted to100 ml to be used as a sample solution. The mixed liquid ofhexane/2-propanol (1:1) was added to 1 ml of this sample solution, andthe total volume was adjusted to 100 ml to be used as a standardsolution. A 10 μl portion of each of the sample solution and standardsolution was tested by a liquid chromatography under the followingconditions, respective peak areas of the respective solutions weremeasured by an automatic integration method, and the amount ofimpurities was calculated by the following equation.Percentage content of respective impurities (%)=ATi/AS[In the formula, ATi represents peak areas of respective impurities ofthe sample solution, and AS represents peak area of solifenacin of thestandard solution.]<Test Conditions>

-   Detector: ultraviolet absorptiometer (measuring wavelength: 220 nm)-   Column: CHIRALPAK AD-H (250 mm×4.6 mm ID, mfd. by Daicel Chemical)-   Column temperature: 20° C.-   Mobile phase: hexane/2-propanol/diethylamine mixed liquid    (800:200:1)-   Flow rate: adjusted such that retention time of solifenacin becomes    about. 35 minutes (about 1 ml/min)

Reference Example 2

A mixture of 360 liters of water and 83.2 kg of potassium carbonate wasadded to a mixture of 120 kg of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 600 liters of toluene,and after cooling to 10° C., 65.3 kg of ethyl chloroformate was addeddropwise thereto and stirred at 25° C. for 2 hours. The water layer wasseparated and the organic layer was washed with 360 liters of water.After evaporation of 290 liters of the solvent under a reduced pressure,1320 liters of toluene and 81 liters of DMF were added thereto, and 87.5kg of (R)-quinuclidin-3-ol and 7.8 kg of sodium ethoxide were addedthereto at room temperature and heated for 8 hours while evaporating thesolvent. A 480 liter portion of toluene and 400 liters of water wereadded to this reaction solution which was subsequently cooled to roomtemperature, and then the water layer was separated and the organiclayer was washed with 400 liters of water. This organic layer was thenextracted with 77.4 kg of concentrated hydrochloric acid and 440 litersof water, the thus obtained water layer was mixed with a mixture of126.8 kg of potassium carbonate and 320 liters of water and extractedwith 810 liters of EtOAc. This organic layer was washed with 160 litersof water and then mixed with 160 liters of EtOH and 240 liters of EtOAc.A 820 liter portion of the solvent of this solution was evaporated byatmospheric distillation to obtain 527.8 kg of an EtOAc solutioncontaining solifenacin.

The optical isomer content of solifenacin of the solifenacin-containingEtOAc solution obtained in Reference Example 2 is shown in Table 1 asthe percentage content when solifenacin is defined as 100%. Also,measured data of the determination of the composition concerningcompound A, compound B and compound C as optical isomers of solifenacinof the solifenacin-containing EtOAc solution obtained in ReferenceExample 2 is shown in FIG. 2.

The content of compound D of the solifenacin obtained in ReferenceExample 2 is shown in Table 2 as the percentage content when solifenacinis defined as 100%.

In this connection, the compound D has the following structure.

In this connection, determination of the compound D was carried out bythe following method.

A 0.05 g portion of the composition obtained in the aforementionedReference Example 2 was dissolved in a liquid prepared by adding 300 mlof acetonitrile to 700 ml of a liquid which had been prepared bydissolving 8.7 g of dipotassium hydrogenphosphate in 1000 ml of waterand adjusted to pH 6.0 by adding phosphoric acid (to be referred to asliquid P hereinafter), and the total volume was adjusted to 100 ml to beused as a sample solution. The liquid P was added to 1 ml of this samplesolution, and the total volume was adjusted to 100 ml to be used as astandard solution. A 10 μl portion of each of the sample solution andstandard solution was tested by a liquid chromatography under thefollowing conditions, respective peak areas of the respective solutionswere measured by an automatic integration method, and the amount ofimpurities was calculated by the following equation.Percentage content of respective impurities (%)=ADTi/ADS[In the formula, ADTi represents peak areas of respective impurities ofthe sample solution, and ADS represents peak area of solifenacin of thestandard solution.]<Test Conditions>

-   Detector: ultraviolet absorptiometer (measuring wavelength: 210 nm)-   Column: Develosil ODS-UG-5 (150 mm×4.6 mm ID, mfd. by Nomura    Chemical) or an equivalent column-   Column temperature: 40° C.-   Mobile phase: a liquid prepared by adding 200 ml of acetonitrile,    100 ml of 2-propanol and 50 ml of methanol to 650 ml of a liquid    which had been prepared by dissolving 8.7 g of dipotassium    hydrogenphosphate in 1000 ml of water and adjusted to pH 6.0 by    adding phosphoric acid-   Flow rate: about 1 ml/min

Reference Example 3

A solifenacin solution containing1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid2-methylquinuclidin-3-yl ester (to be referred to as “compound E”hereinafter) was obtained by allowing 9.00 g of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid methylester to react with 5.14 g of (R)-quinuclidin-3-ol for 8 hours in amixture of 90 ml of toluene and 4.5 ml of DMF in the presence of 0.36 gof sodium methoxide, while evaporating the solvents.

The content of compound E of the solifenacin obtained in ReferenceExample 3 is shown in Table 2 as the percentage content when solifenacinis defined as 100%.

In this connection, determination of the compound E was carried out bythe following method.

A 0.01 g portion of the composition obtained in the aforementionedReference Example 3 was dissolved in the liquid P, and the total volumewas adjusted to 10 ml to be used as a sample solution. A 10 μl portionof this sample solution was tested by a liquid chromatography under thefollowing conditions, and the peak area was measured by an automaticintegration method.

<Test Conditions>

-   Detector: ultraviolet absorptiometer (measuring wavelength: 210 nm)-   Column: Develosil ODS-UG-5 (150 mm×4.6 mm ID, mfd. by Nomura    Chemical)-   Column temperature: 40° C.-   Mobile phase: liquid P-   Flow rate: about 1 ml/min

Reference Example 4

A 25.0 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 24.5g of benzyl chloride carbonate were added to a mixture of 125 ml oftoluene, 19.8 g of potassium carbonate and 75 ml of water and stirred at20° C. for 4 hours, and the organic layer was washed with 75 ml ofwater. The thus obtained organic layer was concentrated under a reducedpressure, purified by a silica gel column chromatography and then driedto obtain 38.0 g of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzylester (¹H-NMR (DMSO-d₆, tetramethylsilane internal standard): δ2.73-2.83 (1H, m), 2.84-2.94 (1H, m), 3.31-3.41 (1H, m), 3.86-3.96 (1H,m), 5.12 (1H, d, J=12.8 Hz), 5.18 (1H, d, J=12.8 Hz), 6.28 (1H, s),7.10-7.38 (14H, m), mass spectrum: m/z=344 [M+H]⁺ (FAB)).

In a mixture of sodium benzyl alkoxide prepared from 0.19 g of benzylalcohol and 0.04 g of metallic sodium with 15 ml of toluene and 0.75 mlof DMF, 1.33 g of (R)-quinuclidin-3-ol was allowed to react with 3.00 gof (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzylester for 8 hours while evaporating the solvents, thereby obtaining 1.38g of 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid2-benzylquinuclidin-3-yl ester (to be referred to as “compound F”hereinafter).

The content of compound F of the solifenacin obtained in ReferenceExample 4 is shown in Table 2 as the percentage content when solifenacinis defined as 100%.

In this connection, determination of the compound F was carried out bythe following method.

A 0.03 g portion of the composition obtained in the aforementionedReference Example 4 was mixed with the liquid P, and the total volumewas adjusted to 10 ml to be used as a sample solution. The liquid P wasadded to 1 ml of this sample solution, and the total volume was adjustedto 200 ml to be used as a standard solution. A 20 μl portion of thesample solution and standard solution was tested by a liquidchromatography under the following conditions, respective peak areas ofthe respective solutions were measured by an automatic integrationmethod, and the amount of impurities was calculated by the followingequation.Percentage content of respective impurities (%)=ATi/AS/2[In the formula, ATi represents peak areas of respective impurities ofthe sample solution, and AS represents peak area of solifenacin of thestandard solution.]<Test Conditions>

-   Detector: ultraviolet absorptiometer (measuring wavelength: 210 nm)-   Column: ODS-A,A-302 (150 mm×4.6 mm ID, mfd. by YMC)-   Column temperature: 40° C.-   Mobile phase: liquid P-   Flow rate: about 1 ml/min

Example 1A

A 4.26 g portion of 1,1′-carbonyldiimidazole was added to 5.00 g of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 25 ml of toluene andstirred at room temperature for 30 minutes. By adding 25 ml of waterthereto, the water layer was separated, the organic layer was washedwith 25 ml of water, and the solvent was evaporated under a reducedpressure. A 10 ml portion of toluene was added to the residue. Thissolution was added dropwise at room temperature to a solution preparedby adding 1.00 g of sodium hydride to a mixture of 3.65 g of(R)-quinuclidin-3-ol, 25 ml of toluene and 5 ml of DMF and heating to100° C., and 5 ml of toluene was further added thereto. This was heatedat 110° C. for 3 hours, cooled and mixed with 25 ml of water, and thewater layer was separated. This was again washed with 25 ml of water,and the organic layer was extracted with a mixture of 3.25 g ofconcentrated hydrochloric acid and 18 ml of water. 34 ml of EtOAc, and amixture of 5.28 g of potassium carbonate and 14 ml of water were addedto the thus obtained water layer, the thus obtained organic layer waswashed with 7 ml of water, and then the solvent was evaporated under areduced pressure to obtain solifenacin.

The thus obtained solifenacin was mixed with 12 ml of EtOH, 28 ml ofEtOAc and 2.74 g of succinic acid, heated, cooled to 30° C. and thenagain heated to 50° C. This was kept at 50° C. for 2 hours and thencooled to 0° C. spending 5 hours, and the precipitated crystals werecollected by filtration, washed twice with 8 ml of EtOAc and then driedunder a reduced pressure to obtain 9.013 g of solifenacin succinate.

The optical isomer content of the solifenacin before salt formation withsuccinic acid, obtained in Example 1A is shown in Table 1 as thepercentage content when solifenacin is defined as 100%. Also, measureddata of the determination of the composition concerning compound A,compound B and compound C of the solifenacin before salt formation withsuccinic acid, obtained in Example 1A is shown in FIG. 3.

Example 1B

A 2.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 0.48g of triethylamine were dissolved in 20 ml of toluene, 1.42 g oftriphosgene was gradually added thereto, and this was stirred at roomtemperature for 2 hours. A 0.60 g portion of triethylamine was furtheradded to this reaction solution and stirred overnight. A 10 ml portionof methanol and 20 ml of water were added to this reaction solution, andthe water layer was separated. The organic layer was washed with 20 mlof water, and the thus obtained organic layer was concentrated under areduced pressure, thereby obtaining an oily substance.

A 1.46 g of (R)-quinuclidin-3-ol was dissolved in 15 ml of toluene, 0.46g of sodium hydride was added thereto under reflux, a solution preparedby dissolving the oily substance obtained in the above in 10 ml oftoluene was gradually added dropwise thereto, and this was refluxedovernight to confirm that solifenacin was formed.

Example 2

A mixture of 3.47 g of potassium carbonate and 15 ml of water was addedto 5.00 g of (RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 25 ml oftoluene, this was cooled to 15° C., 2.72 g of ethyl chloroformate wasadded dropwise thereto, and this was stirred at 25° C. for 1 hour. Thewater layer was separated, the organic layer was washed with 15 ml ofwater, and the solvent was evaporated under a reduced pressure.

A 67 ml portion of toluene, 3 ml of DMF, 3.65 g of (R)-quinuclidin-3-oland 0.33 g of sodium ethoxide were added to the thus obtained residueand heated for 8 hours while evaporating the solvent. The reactionliquid was cooled, washed by adding 20 ml of toluene and 17 ml of waterand again washed with 17 ml of water, and then the organic layer wasextracted with a mixture of 3.25 g of concentrated hydrochloric acid and18 ml of water. 34 ml of EtOAc, and a mixture of 5.28 g of potassiumcarbonate and 14 ml of water were added to the thus obtained waterlayer, and the thus obtained organic layer was washed with 7 ml ofwater, and then the solvent was evaporated under a reduced pressure,thereby obtaining(1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester.

A 6 ml portion of EtOH, 14 ml of EtOAc and 1.30 g of succinic acid wereadded to the thus obtained(1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid(3R)-quinuclidin-3-yl ester, dissolved by heating and cooled to 50° C.,and then 0.003 g of seed crystal of solifenacin succinate produced inthe same manner as in Example 1A was added thereto. This mixture wascooled to 30° C., and then again heated to 50° C. This was kept at 50°C. for 2 hours and then cooled to 0° C. spending 5 hours, and theprecipitated crystals were collected by filtration, washed twice with 10ml of EtOAc and then dried under a reduced pressure to obtain 2.855 g ofsolifenacin succinate as colorless crystals.

In addition, the filtrate after collecting the precipitated crystals byfiltration was concentrated under a reduced pressure, and the residuewas mixed with 10 ml of toluene and again concentrated under a reducedpressure. A 20 ml portion of toluene was added to this residue, amixture of 5.00 g of potassium carbonate and 10 ml of water was addedthereto, and the thus obtained organic layer was washed with 10 ml ofwater and concentrated under a reduced pressure. The residue was mixedwith 30 ml of toluene and 1.91 g of potassium tert-butoxide, stirred at100° C. for 5 hours, cooled and then washed twice with 15 ml of water,and the thus obtained organic layer was concentrated under a reducedpressure. This was mixed with 5 ml of EtOH, 11 ml of EtOAc and 1.11 g ofsuccinic acid, dissolved by heating and cooled to 40° C., and then 0.002g of seed crystal of solifenacin succinate produced in the same manneras in Example 1A was added thereto. This mixture was cooled to 0° C.,and the precipitated crystals were collected by filtration, washed with10 ml of EtOAc and then dried under a reduced pressure to obtain 1.263 gof solifenacin succinate as colorless crystals.

The optical isomer content of the solifenacin succinate obtained inExample 2 is shown in Table 1 as the percentage content when solifenacinis defined as 100%. Also, measured data of the determination of thecomposition concerning compound A, compound B and compound C of thesolifenacin obtained in Example 2 is shown in FIG. 4.

TABLE 1 Reference Reference Example 1A Example 2 Example 1 Example 2Compound A 0.07 0.27 7.35 4.51 Compound B 0.74 0.11 1.70 2.33 Compound CND ND 0.04 0.14

In this connection, the “ND” in the table means detection limit or lessand shows about 0.005% or less.

Example 3

In 100 ml of chloroform and in the presence of 16 g of triethylamine and0.1 g of 4-dimethylaminopyridine, 12.8 g of ethyl chloroformate wasadded to 10.0 g of (R)-quinuclidin-3-ol at 10° C. This was heated to 20°C., stirred for 2 hours and mixed with 50 ml of water, the thus obtainedorganic layer was washed with 50 ml of water, and then the organic layerwas concentrated under a reduced pressure and dried in vacuo to obtain15.49 g of a oily substance. By purifying this oily substance by asilica gel column chromatography, 7.24 g of ethyl (R)-quinuclidin-3-ylcarbonate was obtained (¹H-NMR (DMSO-d₆, tetramethylsilane internalstandard): δ 1.21 (3H, t, J=7.2 Hz), 1.26-1.37 (1H, m), 1.42-1.53 (1H,m), 1.55-1.70 (2H, m), 1.91-1.98 (1H, m), 2.48-2.76 (5H, m), 3.06-3.17(1H, m), 4.11 (2H, q, J=7.2 Hz), 4.56-4.64 (1H, m), mass spectrum:m/z=200 [M+H]⁺ (FAB)).

In a mixture of 10 ml of toluene and 0.5 ml of DMF and in the presenceof 0.21 g of sodium ethoxide, 1.00 g of ethyl (R)-quinuclidin-3-ylcarbonate and 1.05 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline werestirred for 7 hours while evaporating the solvent, 20 ml of toluene and20 ml of water were added thereto, and the thus obtained organic layerwas washed with 20 ml of water and then mixed with 15 ml of 1 Mhydrochloric acid aqueous solution. A 30 ml portion of EtOAc and 1 Msodium hydroxide aqueous solution were added to the obtained waterlayer. The thus obtained organic layer was dried with sodium sulfate,concentrated under a reduced pressure and then dried, and the thusobtained solid was purified by a silica gel column chromatography toobtain 0.22 g of solifenacin.

¹H-NMR (DMSO-d₆, tetramethylsilane internal standard, 80° C.): δ1.25-1.38 (1H, m), 1.41-1.53 (1H, m), 1.53-1.65 (1H, m), 1.66-1.77 (1H,m), 1.87-1.96 (1H, m), 2.40-2.96 (7H, m), 3.00-3.15 (1H, m), 3.33-3.45(1H, m), 3.82-3.92 (1H, m), 4.62-4.69 (1H, m), 6.26 (1H, s), 7.12-7.33(9H, m).

Mass spectrum: m/z=363 [M +H]⁺ (FAB)

Example 4A

A 15.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and9.22 g of isopropyl chloroformate were added to a mixture of 75 ml oftoluene, 10.43 g of potassium carbonate and 45 ml of water and stirredat 20° C. for 2 hours, and then the organic layer was washed with 50 mlof water. The thus obtained organic layer was concentrated under areduced pressure and then dried to obtain 21.71 g of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acidpropan-2-yl ester (¹H-NMR (DMSO-d₆, tetramethylsilane internal standard,80° C.): δ 1.18 (3H, d, J=6.4 Hz), 1.22 (3H, d, J=6.4 Hz), 2.73-2.93(2H, m), 3.25-3.34 (1H, m), 3.83-3.92 (1H, m), 4.80-4.91 (1H, m), 6.22(1H, s), 7.06-7.33 (9H, m), mass spectrum: m/z=296 [M +H]⁺ (FAB)).

In a mixture of sodium isopropoxide prepared from 0.20 g of 2-propanoland 0.08 g of metallic sodium with 20 ml of toluene and 2.5 ml of DMF,2.58 g of (R)-quinuclidin-3-ol was allowed to react with 5.00 g of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acidpropan-2-yl ester for 8 hours while evaporating the solvent, therebyobtaining 3.97 g of a solifenacin-containing composition.

A compound in which isopropyl or the like lower alkyl is added to the2-position of quinuclidine in solifenacin, like the case found inReference Example 2, Reference Example 3 and Reference Example 4, wasnot contained in the solifenacin-containing composition obtained inExample 4A.

In this connection, determination of the composition of this compositionwas carried out by the following method.

A 0.01 g portion of the solifenacin-containing composition obtained inthe aforementioned Example 4A was dissolved in a solution which had beenprepared by dissolving 6.1 g of sodium perchlorate in, adjusting this to1000 ml and adjusting its pH to 2.0 by adding perchloric acid (to bereferred to as liquid Q hereinafter), and the total volume was adjustedto 10 ml to be used as a sample solution. A 10 μl portion of this samplesolution was tested by a liquid chromatography under the followingconditions, and the peak area was measured by an automatic analysismethod.

<Test Conditions>

-   Detector: ultraviolet absorptiometer (measuring wavelength: 210 nm)-   Column: Develosil ODS-UG-5 (150 mm×4.6 mm ID, mfd. by Nomura    Chemical)-   Column temperature: 40° C.-   Mobile phase: liquid Q-   Flow rate: about 1 ml/min

Example 4B

A 10.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and10.41 g of tert-butyl dicarbonate were added to a mixture of 50 ml oftoluene, 6.95 g of potassium carbonate and 30 ml of water and stirred at20° C. overnight, and then the organic layer was washed with 30 ml ofwater. The thus obtained organic layer was concentrated under a reducedpressure and then dried to obtain 14.59 g of(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid2-methylpropan-2-yl ester (¹H-NMR (DMSO-d₆, tetramethylsilane internalstandard, 80° C.): δ 1.39 (9H, s), 2.72-2.91 (2H, m), 3.28-3.32 (1H, m),3.80-3.89 (1H, m), 6.18 (1H, s), 7.07-7.33 (9H, m), mass spectrum:m/z=310 [M +H]⁺ (FAB)).

In a mixture of 0.38 g of sodium tert-butoxide, 60 ml of toluene and 3ml of DMF, 2.96 g of (R)-quinuclidin-3-ol was allowed to react with 6.00g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid2-methylpropan-2-yl ester for 8 hours while evaporating the solvent,thereby obtaining 0.274 g of a solifenacin-containing composition.

A compound in which tert-butyl or the like lower alkyl is added to the2-position of quinuclidine in solifenacin, like the case found inReference Example 2, Reference Example 3 and Reference Example 4, wasnot contained in the solifenacin-containing composition obtained inExample 4B.

In this connection, determination of the composition of this compositionwas carried out in accordance with the determination method of thecomposition obtained in the aforementioned Example 4A.

TABLE 2

Percentage content R^(A) of each compound Reference Example 2 ethyl(compound D) 0.67 Reference Example 3 methyl (compound E) 0.20 ReferenceExample 4 benzyl (compound F) 0.07 Example 4A isopropyl ND Example 4Btert-butyl ND

In this connection, the “ND” in the table means detection limit or lessand shows about 0.005% or less.

1. A method for producing solifenacin or a pharmaceutically acceptablesalt thereof, which is a method for producing solifenacin succinate,which comprises allowing succinic acid to react with a compoundrepresented by a formula (II)

in the formula, stereochemistry of the 1-position of phenyl-substitutedtetrahydroisoquinoline is a mixture of (R)-form and (S)-form.
 2. Amethod for producing solifenacin or a pharmaceutically acceptable saltthereof, which comprises allowing a compound represented by a formula(III)

in the formula, R¹ represents a lower alkyl which may be substituted,and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof toundergo condensation.
 3. A method for producing solifenacin or apharmaceutically acceptable salt thereof, which comprises allowing acompound represented by a formula (IV)

in the formula, R² represents a secondary lower alkyl or a tertiarylower alkyl, which may be respectively substituted, and(R)-quinuclidin-3-ol to undergo reaction in the presence of an alkalimetal lower alkoxide.
 4. The production method described in claim 3,wherein the lower alkoxide of the alkali metal lower alkoxide is asecondary lower alkoxide or a tertiary lower alkoxide.